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The Journal of Emergency Medicine Sep 2021Diphenhydramine, a first generation H histamine receptor antagonist, is a commonly used nonprescription medication that is used for the treatment of allergy, as a sleep...
BACKGROUND
Diphenhydramine, a first generation H histamine receptor antagonist, is a commonly used nonprescription medication that is used for the treatment of allergy, as a sleep aid, or combined with cough and cold remedies. Naproxen, a nonsteroidal anti-inflammatory drug (NSAID), is used commonly for analgesia. Although most cases of diphenhydramine or naproxen overdose require excellent supportive care only, meticulous attention should be given to cardiovascular and neurologic status.
CASE REPORT
A 22-year-old woman presented with altered mental status secondary to intentional ingestion of 240 combination caplets of naproxen sodium 220 mg and diphenhydramine hydrochloride 25 mg. While in the emergency department, she manifested a wide-complex tachycardia in the setting of hypotension that required repeated administration of sodium bicarbonate to overcome the sodium channel blockade caused by diphenhydramine. Aggressive potassium repletion was performed simultaneously. Her clinical course was complicated by status-epilepticus that required intubation. Orogastric lavage was performed, which returned blue pill slurry consistent with the ingested caplets. The patient was extubated on hospital day 2 and transferred to psychiatry thereafter. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: In light of recent social media trends, such as the "Benadryl challenge" and its widespread availability, emergency providers should be familiar with diphenhydramine toxicity, especially the life-threatening neurologic consequences and risk of cardiovascular collapse. NSAIDs, such as naproxen, and other nonprescription analgesics are becoming more and more important in light of the current opioid crisis. There should be an emphasis on understanding these medications and their potential implications when taken in overdose.
Topics: Diphenhydramine; Drug Overdose; Female; Humans; Naproxen; Sodium Bicarbonate; Tachycardia; Young Adult
PubMed: 34148773
DOI: 10.1016/j.jemermed.2021.04.020 -
Comparative Biochemistry and... Aug 2019Acetylcholinesterase (AChE) plays an important role in the therapy of Alzheimer's disease and in the detection of pesticides such as organophosphates which are also...
Acetylcholinesterase (AChE) plays an important role in the therapy of Alzheimer's disease and in the detection of pesticides such as organophosphates which are also widely used in chemical warfare. The aim of this study is the physicochemical and kinetic characterization of brain and muscle ChE from Danio rerio (Zebrafish). Optimal activity was found for brain ChE at alkaline pH 9.0 at 30 °C, and for muscle ChE at alkaline pH 8.5 at temperatures between 20 °C and 35 °C. The apparent kinetic constants, K and V, for brain ChE were determined as 0.191 ± 0.024 mM and 0.566 ± 0.028 U/mg protein, and for muscle ChE as 0.230 ± 0.030 mM and 0.677 ± 0.039 U/mg protein. Both brain and muscle ChE showed inhibition at high substrate concentrations. Brain and muscle ChE showed IC50 values for physostigmine of 0.61 μM and 0.37 μM, respectively. The ChE activity in brain was significantly inhibited by BW254c51 in all concentrations tested, but not by Iso-OMPA, while muscle ChE presented a moderate decrease (13 to 29%) in the activity values, indicating that BuChE is present.
Topics: Acetylcholinesterase; Animals; Brain; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Hydrogen-Ion Concentration; Muscle, Skeletal; Temperature; Zebrafish
PubMed: 30981910
DOI: 10.1016/j.cbpc.2019.04.005 -
Journal of Biomolecular Structure &... Nov 2023This study delineates the design and synthesis of a series of xanthene-based thiosemicarbazones that show low μM inhibition of acetylcholinesterase (AChE) and...
This study delineates the design and synthesis of a series of xanthene-based thiosemicarbazones that show low μM inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), crucial enzymes associated with, among others, Alzheimer's Disease (AD) pathology. Despite FDA-approved AChE inhibitors being frontline treatments for AD, there remains a need for agents exhibiting improved efficacy and selectivity. Our synthesized series demonstrate meaningful inhibition against AChE (IC50 ranging from 4.2 to 62 μM). These compounds exhibit comparatively lower potency against BChE (IC50 values between 64 and 315 μM), showcasing a pronounced AChE selectivity compared to physostigmine. The selectivity index for the compounds between the two targets does vary between 0.02 and 0.75 highlighting that even minor structural differences can have drastic effects on protein interactions. Molecular docking insights further substantiated these observations, revealing the importance of the xanthene scaffold for AChE-binding and the aryl R moiety for BChE interactions. Notably, some compounds demonstrated dual enzyme targeting, emphasizing their interactions could be exploited for developing monotherapies against cholinesterase-associated neurodegenerative afflictions like AD. Collectively, these findings suggest that xanthene-based thiosemicarbazones are a promising and highly accessible scaffold that deserve further investigative exploration in the cholinesterase inhibitor therapeutic landscape.Communicated by Ramaswamy H. Sarma.
PubMed: 37948312
DOI: 10.1080/07391102.2023.2274981 -
Scientific Reports Dec 2022The Alzheimer's disease-associated peptide amyloid-beta (Aβ) has been associated with neuronal hyperactivity under anesthesia, but clinical trials of anticonvulsants or...
The Alzheimer's disease-associated peptide amyloid-beta (Aβ) has been associated with neuronal hyperactivity under anesthesia, but clinical trials of anticonvulsants or neural system suppressors have, so far, failed to improve symptoms in AD. Using simultaneous hippocampal calcium imaging and electrophysiology in freely moving mice expressing human Aβ, here we show that Aβ aggregates perturbed neural systems in a state-dependent fashion, driving neuronal hyperactivity in exploratory behavior and slow wave sleep (SWS), yet suppressing activity in quiet wakefulness (QW) and REM sleep. In exploratory behavior and REM sleep, Aβ impaired hippocampal theta-gamma phase-amplitude coupling and altered neuronal synchronization with theta. In SWS, Aβ reduced cortical slow oscillation (SO) power, the coordination of hippocampal sharp wave-ripples with both the SO and thalamocortical spindles, and the coordination of calcium transients with the sharp wave-ripple. Physostigmine improved Aβ-associated hyperactivity in exploratory behavior and hypoactivity in QW and expanded the range of gamma that coupled with theta phase, but exacerbated hypoactivity in exploratory behavior. Together, these findings show that the effects of Aβ alone on hippocampal circuit function are profoundly state dependent and suggest a reformulation of therapeutic strategies aimed at Aβ induced hyperexcitability.
Topics: Animals; Humans; Mice; Alzheimer Disease; Amyloid beta-Peptides; Calcium; Disease Models, Animal; Hippocampus; Mice, Transgenic
PubMed: 36471155
DOI: 10.1038/s41598-022-25364-2 -
British Journal of Clinical Pharmacology Jan 2022
Topics: Cholinesterase Inhibitors; Humans; Muscarinic Antagonists; Physostigmine
PubMed: 34784063
DOI: 10.1111/bcp.15121 -
Neurogastroenterology and Motility Mar 2022This systematic review and meta-analysis aimed to evaluate the effects of pharmacological agents for neurogenic oropharyngeal dysphagia based on evidence from randomized... (Meta-Analysis)
Meta-Analysis
BACKGROUND
This systematic review and meta-analysis aimed to evaluate the effects of pharmacological agents for neurogenic oropharyngeal dysphagia based on evidence from randomized controlled trials (RCTs).
METHODS
Electronic databases were systematically searched between January 1970 and March 2021. Two reviewers independently extracted and synthesized the data. The outcome measure was changed in (any) relevant clinical swallowing-related characteristics.
KEY RESULTS
Data from 2186 dysphagic patients were collected from 14 RCT studies across a range of pharmacotherapies. The pooled effect size of transient receptor potential (TRP) channel agonists was large compared to placebo interventions (SMD[95%CI] =1.27[0.74,1.80], p < 0.001; I = 79%). Data were limited for other pharmacological agents and the overall pooled effect size of these agents was non-significant (SMD [95% CI] =0.25 [-0.24, 0.73]; p = 0.31; I = 85%). When analyzed separately, large effect sizes were observed with Nifedipine (SMD[95%CI] =1.13[0.09,2.18]; p = 0.03) and Metoclopramide (SMD[95%CI] =1.68[1.08,2.27]; p < 0.001). By contrast, the effects of angiotensin-converting enzyme (ACE) inhibitors (SMD[95%CI] = -0.67[-2.32,0.99]; p = 0.43; I = 61%), Physostigmine (SMD[95%CI] = -0.05[-1.03,0.93]; p = 0.92) and Glyceryl Trinitrate (GTN) (SMD [95% CI] = -0.01 [-0.11, 0.08]; p = 0.78) were non-significant. Within stroke patients, subgroup analysis showed that TRP channel agonists had a moderate pooled effect size (SMD[95%CI] =0.74[0.10,1.39]; p = 0.02; I = 82%) whereas the effects of other agents were non-significant (SMD[95%CI] =0.40[-0.04,0.84]; p = 0.07; I = 87%).
CONCLUSIONS & INFERENCES
Our results showed that TRP channel agonists, Nifedipine and Metoclopromide may be beneficial for neurogenic dysphagic patients. Large scale, multicenter clinical trials are warranted to fully explore their therapeutic effects on swallowing.
Topics: Deglutition; Deglutition Disorders; Humans; Multicenter Studies as Topic; Nifedipine; Stroke
PubMed: 34337829
DOI: 10.1111/nmo.14220 -
Nature Communications Sep 2021Aliphatic esters are essential constituents of biologically active compounds and versatile chemical intermediates for the synthesis of drugs. However, their preparation...
Aliphatic esters are essential constituents of biologically active compounds and versatile chemical intermediates for the synthesis of drugs. However, their preparation from readily available olefins remains challenging. Here, we report a strategy to access aliphatic esters from olefins through a photocatalyzed alkoxycarbonylation reaction. Alkyloxalyl chlorides, generated in situ from the corresponding alcohols and oxalyl chloride, are engaged as alkoxycarbonyl radical fragments under photoredox catalysis. This transformation tolerates a broad scope of electron-rich and electron-deficient olefins and provides the corresponding β-chloro esters in good yields. Additionally, a formal β-selective alkene alkoxycarbonylation is developed. Moreover, a variety of oxindole-3-acetates and furoindolines are prepared in good to excellent yields. A more concise formal synthesis of (±)-physovenine is accomplished as well. With these strategies, a wide range of natural-product-derived olefins and alkyloxalyl chlorides are also successfully employed.
Topics: Alcohols; Alkenes; Catalysis; Chemistry Techniques, Synthetic; Chlorides; Esters; Humans; Indoles; Molecular Structure; Oxalates; Oxidation-Reduction; Oxindoles; Photochemical Processes; Physostigmine; Stereoisomerism
PubMed: 34493725
DOI: 10.1038/s41467-021-25628-x -
Microbial Cell Factories Aug 2021Melatonin has attracted substantial attention because of its excellent prospects for both medical applications and crop improvement. The microbial production of...
BACKGROUND
Melatonin has attracted substantial attention because of its excellent prospects for both medical applications and crop improvement. The microbial production of melatonin is a safer and more promising alternative to chemical synthesis approaches. Researchers have failed to produce high yields of melatonin in common heterologous hosts due to either the insolubility or low enzyme activity of proteins encoded by gene clusters related to melatonin biosynthesis.
RESULTS
Here, a combinatorial gene pathway for melatonin production was successfully established in Escherichia coli by combining the physostigmine biosynthetic genes from Streptomyces albulus and gene encoding phenylalanine 4-hydroxylase (P4H) from Xanthomonas campestris and caffeic acid 3-O-methyltransferase (COMT) from Oryza sativa. A threefold improvement of melatonin production was achieved by balancing the expression of heterologous proteins and adding 3% glycerol. Further protein engineering and metabolic engineering were conducted to improve the conversion of N-acetylserotonin (NAS) to melatonin. Construction of COMT variant containing C303F and V321T mutations increased the production of melatonin by fivefold. Moreover, the deletion of speD gene increased the supply of S-adenosylmethionine (SAM), an indispensable cofactor of COMT, which doubled the yield of melatonin. In the final engineered strain EcMEL8, the production of NAS and melatonin reached 879.38 ± 71.42 mg/L and 136.17 ± 1.33 mg/L in a shake flask. Finally, in a 2-L bioreactor, EcMEL8 produced 1.06 ± 0.07 g/L NAS and 0.65 ± 0.11 g/L melatonin with tryptophan supplementation.
CONCLUSIONS
This study established a novel combinatorial pathway for melatonin biosynthesis in E. coli and provided alternative strategies for improvement of melatonin production.
Topics: Escherichia coli; Melatonin; Metabolic Engineering; Protein Engineering
PubMed: 34454478
DOI: 10.1186/s12934-021-01662-8 -
Chemistry & Biodiversity Aug 2023Cinnamomum species have applications in the pharmaceutical and fragrance industry for wide biological and pharmaceutical activities. The present study investigates the...
Cinnamomum species have applications in the pharmaceutical and fragrance industry for wide biological and pharmaceutical activities. The present study investigates the chemical composition of the essential oils extracted from two species of Cinnamomum namely C. tamala and C. camphora. Chemical analysis showed E-cinnamyl acetate (56.14 %), E-cinnamaldehyde (20.15 %), and linalool (11.77 %) contributed as the major compounds of the 95.22 % of C. tamala leaves essential oil found rich in phenylpropanoids (76.96 %). C. camphora essential oil accounting for 93.57 % of the total oil composition was rich in 1,8-cineole (55.84 %), sabinene (14.37 %), and α-terpineol (10.49 %) making the oil abundant in oxygenated monoterpenes (70.63 %). Furthermore, the acetylcholinesterase inhibitory activity for both the essential oils was carried out using Ellman's colorimetric method. The acetylcholinesterase inhibitory potential at highest studied concentration of 1 mg/mL was observed to be 46.12±1.52 % for C. tamala and 53.61±2.66 % for C. camphora compared to the standard drug physostigmine (97.53±0.63 %) at 100 ng/ml. These multiple natural aromatic and fragrant characteristics with distinct chemical compositions offered by Cinnamon species provide varied benefits in the development of formulations that could be advantageous for the flavor and fragrance industry.
Topics: Cinnamomum camphora; Cinnamomum; Acetylcholinesterase; Oils, Volatile; Pharmaceutical Preparations; Plant Leaves
PubMed: 37533252
DOI: 10.1002/cbdv.202300666 -
BMJ Open May 2023Preoperative hypoalbuminaemia is associated with adverse outcome, including increased postoperative mortality in cardiovascular surgery, neurosurgery, trauma and... (Observational Study)
Observational Study
OBJECTIVES
Preoperative hypoalbuminaemia is associated with adverse outcome, including increased postoperative mortality in cardiovascular surgery, neurosurgery, trauma and orthopaedic surgery. However, much less is known about the association between preoperative serum albumin and clinical outcomes after liver surgery. In this study, we sought to determine whether hypoalbuminaemia before partial hepatectomy is associated with a worse postoperative outcome.
DESIGN
Observational study.
SETTING
University Medical Centre in Germany.
PARTICIPANTS
We analysed 154 patients enrolled in the perioperative PHYsostigmine prophylaxis for liver resection patients at risk for DELIrium and postOperative cognitive dysfunction (PHYDELIO) trial with a preoperative serum albumin assessment. Hypoalbuminaemia was defined as serum albumin <35 g/L. Subgroups classified as hypoalbuminaemia and non-hypoalbuminaemia consisted of 32 (20.8%) and 122 (79.2%) patients, respectively.
OUTCOME MEASURES
The outcome parameters of interest were postoperative complications according to Clavien (moderate: I, II; major: ≥III), length of intensive care unit (ICU) stay, length of hospital stay and survival rates 1 year after surgery.
RESULTS
Preoperative hypoalbuminaemia was associated with the occurrence of major postoperative complications (OR 3.051 (95% CI 1.197 to 7.775); p=0.019) after adjusting for age, sex, randomisation, American Society of Anesthesiologists physical status, preoperative diagnosis and Child-Pugh class. Both ICU and hospital lengths of stay were significantly prolonged in patients with preoperative hypoalbuminaemia (OR 2.573 (95% CI 1.015 to 6.524); p=0.047 and OR 1.296 (95% CI 0.254 to 3.009); p=0.012, respectively). One-year survival was comparable between patients with and without hypoalbuminaemia.
CONCLUSIONS
We found that low serum albumin before surgery was associated with a worse short-term outcome after partial hepatectomy, which strengthens the prognostic value of serum albumin in the setting of liver surgery.
TRIAL REGISTRATION NUMBERS
ISRCTN18978802 and EudraCT 2008-007237-47.
Topics: Humans; Risk Factors; Hypoalbuminemia; Postoperative Complications; Serum Albumin; Liver; Academic Medical Centers
PubMed: 37202140
DOI: 10.1136/bmjopen-2022-068405